BACKGROUND Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved. METHODS Here, we assessed the consequences of CX3CL1 knockout (CX3CL1-/-) on cognitive behavior as well as the functional rescue with the two different forms of CX3CL1 in mice. CX3CL1-/- mice were treated with adeno-associated virus (AAV) expressing either green fluorescent protein (GFP), sFKN, or an obligate membrane-bound form of CX3CL1 (mFKN) and then subjected to behavioral testing to assess cognition and motor function. Following behavioral analysis, brains were collected and analyzed for markers of neurogenesis, or prepared for electrophysiology to measure long-term potentiation (LTP) in hippocampal slices. RESULTS CX3CL1-/- mice showed significant deficits in cognitive tasks for long-term memory and spatial learning and memory in addition to demonstrating enhanced basal motor performance. These alterations correlated with deficits in both hippocampal neurogenesis and LTP. Treatment of CX3CL1-/- mice with AAV-sFKN partially corrected changes in both cognitive and motor function and restored neurogenesis and LTP to levels similar to wild-type animals. Treatment with AAV-mFKN partially restored spatial learning and memory in CX3CL1-/- mice, but did not rescue long-term memory, or neurogenesis. CONCLUSIONS These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.

中文翻译：

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CX3CL1的两种形式在CX3CL1基因敲除小鼠中表现出不同的活性并挽救认知缺陷。

背景技术Fractalkine（CX3CL1; FKN）是由神经元表达的趋化因子，介导神经元和小胶质细胞之间的通讯。通过调节小胶质细胞活性，CX3CL1可以减轻大脑内慢性小胶质细胞炎症的破坏作用，这种状态在衰老和神经退行性变中起主要作用。CX3CL1以两种形式存在，即全长膜结合形式和可溶性裂解形式（sFKN），由整合素和金属蛋白酶（ADAM）10或17产生。sFKN的水平随着衰老而降低，这可能导致炎症加剧，突触重塑缺陷以及随后的认知能力下降。最近，这两种形式的CX3CL1可能在中枢神经系统内表现出不同活性的想法引起了越来越多的关注，但仍未得到解决。方法在这里，我们评估了CX3CL1敲除（CX3CL1-/-）对认知行为以及小鼠中两种不同形式的CX3CL1的功能性抢救的后果。用表达绿色荧光蛋白（GFP），sFKN或专一性膜结合形式的CX3CL1（mFKN）的腺相关病毒（AAV）处理CX3CL1-/-小鼠，然后进行行为测试以评估认知和运动功能。进行行为分析后，收集大脑并分析神经发生的标志物，或准备进行电生理学以测量海马切片中的长期增强（LTP）。结果CX3CL1-/-小鼠除了表现出增强的基础运动表现外，在长期记忆，空间学习和记忆的认知任务中也表现出明显的缺陷。这些改变与海马神经发生和LTP的缺陷有关。用AAV-sFKN治疗CX3CL1-/-小鼠可部分纠正认知和运动功能的变化，并将神经发生和LTP恢复到与野生型动物相似的水平。用AAV-mFKN治疗可部分恢复CX3CL1-/-小鼠的空间学习和记忆能力，但不能挽救长期记忆或神经发生。结论这些结果是第一个证明CX3CL1基因敲除会导致明显的认知缺陷的方法，可以通过sFKN的治疗来挽救，而仅通过mFKN的治疗来挽救。这表明恢复CX3CL1可溶性形式信号传导的治疗可能是衰老和疾病的可行治疗选择。用AAV-sFKN治疗CX3CL1-/-小鼠可部分纠正认知和运动功能的变化，并将神经发生和LTP恢复到与野生型动物相似的水平。用AAV-mFKN治疗可部分恢复CX3CL1-/-小鼠的空间学习和记忆能力，但不能挽救长期记忆或神经发生。结论这些结果是第一个证明CX3CL1基因敲除会引起明显的认知缺陷的方法，可以通过sFKN治疗来弥补，而仅通过mFKN来解决。这表明恢复CX3CL1可溶性形式信号传导的治疗可能是衰老和疾病的可行治疗选择。用AAV-sFKN治疗CX3CL1-/-小鼠可部分纠正认知和运动功能的变化，并将神经发生和LTP恢复到与野生型动物相似的水平。用AAV-mFKN治疗可部分恢复CX3CL1-/-小鼠的空间学习和记忆能力，但不能挽救长期记忆或神经发生。结论这些结果是第一个证明CX3CL1基因敲除会引起明显的认知缺陷的方法，可以通过sFKN治疗来弥补，而仅通过mFKN来解决。这表明恢复CX3CL1可溶性形式信号传导的治疗可能是衰老和疾病的可行治疗选择。但没有挽救长期记忆或神经发生。结论这些结果是第一个证明CX3CL1基因敲除会引起明显的认知缺陷的方法，可以通过sFKN治疗来弥补，而仅通过mFKN来解决。这表明恢复CX3CL1可溶性形式信号传导的治疗可能是衰老和疾病的可行治疗选择。但没有挽救长期记忆或神经发生。结论这些结果是第一个证明CX3CL1基因敲除会导致明显的认知缺陷的方法，可以通过sFKN的治疗来挽救，而仅通过mFKN的治疗来挽救。这表明恢复CX3CL1可溶性形式信号传导的治疗可能是衰老和疾病的可行治疗选择。